Incompetence of neutrophils to invasive group A streptococcus is attributed to induction of plural virulence factors by dysfunction of a regulator.
Group A streptococcus (GAS) causes variety of diseases ranging from common pharyngitis to life-threatening severe invasive diseases, including necrotizing fasciitis and streptococcal toxic shock-like syndrome. The characteristic of invasive GAS infections has been thought to attribute to genetic changes in bacteria, however, no clear evidence has shown due to lack of an intriguingly study using serotype-matched isolates from clinical severe invasive GAS infections. In addition, rare outbreaks of invasive infections and their distinctive pathology in which infectious foci without neutrophil infiltration hypothesized us invasive GAS could evade host defense, especially neutrophil functions. Herein we report that a panel of serotype-matched GAS, which were clinically isolated from severe invasive but not from non-invaive infections, could abrogate functions of human polymorphnuclear neutrophils (PMN) in at least two independent ways; due to inducing necrosis to PMN by enhanced production of a pore-forming toxin streptolysin O (SLO) and due to impairment of PMN migration via digesting interleukin-8, a PMN attracting chemokine, by increased production of a serine protease ScpC. Expression of genes was upregulated by a loss of repressive function with the mutation of csrS gene in the all emm49 severe invasive GAS isolates. The csrS mutants from clinical severe invasive GAS isolates exhibited high mortality and disseminated infection with paucity of neutrophils, a characteristic pathology seen in human invasive GAS infection, in a mouse model. However, GAS which lack either SLO or ScpC exhibit much less mortality than the csrS-mutated parent invasive GAS isolate to the infected mice. These results suggest that the abilities of GAS to abrogate PMN functions can determine the onset and severity of invasive GAS infection.
Ato
Manabu
M
Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan.
Ikebe
Tadayoshi
T
Kawabata
Hiroki
H
Takemori
Toshitada
T
Watanabe
Haruo
H
D000818:Animals; D001426:Bacterial Proteins / Q000096:biosynthesis; D006023:Glycoproteins / Q000096:biosynthesis; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007121:Immunocompetence; D016209:Interleukin-8 / Q000032:analysis; D051379:Mice; D050505:Mutant Proteins; D009504:Neutrophils / Q000276:immunology*; D051117:Scavenger Receptors, Class A / Q000235:genetics; D013290:Streptococcal Infections / Q000276:immunology; D013297:Streptococcus pyogenes / Q000276:immunology / Q000472:pathogenicity*; D013301:Streptolysins / Q000096:biosynthesis; D014157:Transcription Factors; D015533:Transcriptional Activation; D015854:Up-Regulation; D037521:Virulence Factors / Q000235:genetics*
D001426:Bacterial Proteins; D006023:Glycoproteins; D006360:Heat-Shock Proteins; D016209:Interleukin-8; D050505:Mutant Proteins; C045283:SAGP protein, Streptococcus; C112525:SCARA3 protein, human; D051117:Scavenger Receptors, Class A; D013301:Streptolysins; D014157:Transcription Factors; D037521:Virulence Factors; C025964:streptolysin O